Deficiency of the ywhaz gene, involved in neurodevelopmental disorders, alters brain activity and behaviour in zebrafish.

Genetic variants in YWHAZ contribute to psychiatric disorders such as autism spectrum disorder and schizophrenia, and have been related to an impaired neurodevelopment in humans and mice. Here, we have used zebrafish to investigate the mechanisms by which YWHAZ contributes to neurodevelopmental disorders. We observed that ywhaz expression was pan-neuronal during developmental stages and restricted to Purkinje cells in the adult cerebellum, cells that are described to be reduced in number and size in autistic patients. We then performed whole-brain imaging in wild-type and ywhaz CRISPR/Cas9 knockout (KO) larvae and found altered neuronal activity and connectivity in the hindbrain. Adult ywhaz KO fish display decreased levels of monoamines in the hindbrain and freeze when exposed to novel stimuli, a phenotype that can be reversed with drugs that target monoamine neurotransmission. These findings suggest an important role for ywhaz in establishing neuronal connectivity during development and modulating both neurotransmission and behaviour in adults.

Commentary: Another layer to the "PPM conundrum".

How do manufacturer estimates of valve performance match up to reality and stress testing? We are reviewing a manuscript by Porterie et al. in the Journal of Cardiac Surgery detailing a single-center, assessment of Avalus™ bioprosthetic valve hemodynamics during stress echocardiography. At maximal stress, they found that indexed effective orifice area had better alignment with manufacturer estimates than measurements at rest. In addition, they found a significant difference between EOA and flow rates at rest versus maximal exertion and quantified it as the "opening reserve." Patients without patient prosthetic mismatch had much higher opening reserves. This interesting study helps us to understand how estimates align with reality and draws attention to the concept of the opening reserve. Could differences in opening flow impact the durability or longevity of prosthetics?

Commentary: The challenges of propensity score matching in cardiac surgery.

The advent of transcatheter valve technology for structural heart disease has led to heightened scrutiny of outcomes following surgical valve replacement. Here, we review a manuscript by Tsubota et al. in the Journal of Cardiac Surgery detailing a single-center, retrospective cohort study of patients undergoing mitral valve replacement from 2007 to 2018. While outcomes appear to be excellent, these results should be carefully interpreted in light of limited data regarding the propensity score match methodology utilized.

Commentary: Thinking inside and outside of the box with intraextracardiac Fontan.

What is the most optimal way to palliate univentricular physiology? We are reviewing a manuscript by Simsek and colleagues in the Journal of Cardiac Surgery-describing their experience with the intraextracardiac Fontan procedure (IECF). They report encouraging early results in 17 patients who underwent the procedure between 2014 and 2021 and clearly describe their operative technique and variant anatomy they encountered. There are now at least four generations of Fontan procedures, each attempting to palliate while maintaining appropriate hemodynamics as long as possible. IECF provides a good option for cavopulmonary bypass as it avoids pitfalls of prior generations. It may be even more favorable in situations with additional anatomic complexity. We look forward to seeing the long-term outcomes of the IECF.

Commentary: Small patients with big wounds.

Some would argue that kids aren't just little adults, but what about their sternums? We are reviewing a manuscript by Horriat, McCandless, and colleagues in the Journal of Cardiac Surgery describing their experience with managing sternal wound infections (SWI) after congenital heart surgery. They report encouraging results in 14 patients who required plastic surgery consultation to manage their sternal wounds. The nature of congenital cardiac abnormalities and the necessary steps to repair them leads to physiologic derangements predisposing patients to SWI. Rates of SWI vary and have been reported at 1.53% in this population. There is little guidance on how the management of the congenital cardiac surgery patient should differ from the adult patient.

Commentary: Extracardiac conduit-total cavopulmonary connection for heterotaxy-Is going the "extra" mile worth it.

Extracardiac conduit-total cavopulmonary connection (EC-TCPC) represents the latest evolution in Fontan palliation for single ventricle physiology. Here, we review a manuscript by Pan et al. in the Journal of Cardiac Surgery detailing a retrospective, single-center cohort study of patients with and without heterotaxy syndrome undergoing EC-TCPC. Although lacking a comparison to other techniques for single ventricle palliation, this approach appears to offer excellent outcomes for this complex patient cohort.

Commentary: Should we "keep rollin'" for PA/VSD/MAPCA?

Pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries (PA/VSD/MAPCA) represents an anatomically diverse and technically demanding spectrum of congenital disease. Here, we review a manuscript by Onalan et al. in the Journal of Cardiac Surgery detailing a retrospective, single-center cohort study of patients undergoing unifocalization for PA/VSD/MAPCA via either a pulmonary artery patch augmentation or pericardial roll technique. While they report statistically equivalent outcomes using both techniques, longer follow-up and increased sample size are necessary to determine efficacy and safety.

Distracting stimuli evoke ventral tegmental area responses in rats during ongoing saccharin consumption.

Disruptions in attention, salience and increased distractibility are implicated in multiple psychiatric conditions. The ventral tegmental area (VTA) is a potential site for converging information about external stimuli and internal states to be integrated and guide adaptive behaviours. Given the dual role of dopamine signals in both driving ongoing behaviours (e.g., feeding) and monitoring salient environmental stimuli, understanding the interaction between these functions is crucial. Here, we investigate VTA neuronal activity during distraction from ongoing feeding. We developed a task to assess distraction exploiting self-paced licking in rats. Rats trained to lick for saccharin were given a distraction test, in which three consecutive licks within 1 s triggered a random distractor (e.g. light and tone stimulus). On each trial they were quantified as distracted or not based on the length of their pauses in licking behaviour. We expressed GCaMP6s in VTA neurons and used fibre photometry to record calcium fluctuations during this task as a proxy for neuronal activity. Distractor stimuli caused rats to interrupt their consumption of saccharin, a behavioural effect which quickly habituated with repeat testing. VTA neural activity showed consistent increases to distractor presentations and, furthermore, these responses were greater on distracted trials compared to non-distracted trials. Interestingly, neural responses show a slower habituation than behaviour with consistent VTA responses seen to distractors even after they are no longer distracting. These data highlight the complex role of the VTA in maintaining ongoing appetitive and consummatory behaviours while also monitoring the environment for salient stimuli.

Modulation of stimulated dopamine release in rat nucleus accumbens shell by GABA in vitro: Effect of sub-chronic phencyclidine pretreatment.

Dopamine signaling in nucleus accumbens (NAc) is modulated by γ-aminobutyric acid (GABA), acting through GABA-A and GABA-B receptors: dysregulation of GABAergic control of dopamine function may be important in behavioral deficits in schizophrenia. We investigated the effect of GABA-A (muscimol) and GABA-B (baclofen) receptor agonists on electrically stimulated dopamine release. Furthermore, we explored whether drug-induced changes were disrupted by pretreatment with phencyclidine, which provides a well-validated model of schizophrenia. Using brain slices from female rats, fast-scan cyclic voltammetry was used to measure electrically stimulated dopamine release in NAc shell. Both muscimol and baclofen caused concentration-dependent attenuation of evoked dopamine release: neither effect was changed by dihydro-ß-erythroidine, a nicotinic acetylcholine receptor antagonist, or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), precluding indirect mechanisms using these transmitter systems in the GABAergic actions. In slices taken from rats pretreated with phencyclidine, the attenuation of evoked dopamine release by baclofen was abolished, but the attenuation by muscimol was unaffected. Since phencyclidine pretreatment was followed by drug-free washout period of at least a week, the drug was not present during recording. Therefore, disruption of GABA-B modulation of dopamine is due to long-term functional changes resulting from the treatment, rather than transient changes due to the drug's presence at test. This enduring dysregulation of GABA-B modulation of accumbal dopamine release provides a plausible mechanism through which GABA dysfunction influences accumbal dopamine leading to behavioral changes seen in schizophrenia and may provide a route for novel therapeutic strategies to treat the condition.

Synchronization in the prefrontal-striatal circuit tracks behavioural choice in a go-no-go task in rats.

Rodent striatum is involved in sensory-motor transformations and reward-related learning. Lesion studies suggest dorsolateral striatum, dorsomedial striatum and nucleus accumbens underlie stimulus-response transformations, goal-directed behaviour and reward expectation, respectively. In addition, prefrontal inputs likely control these functions. Here, we set out to study how reward-driven behaviour is mediated by the coordinated activity of these structures in the intact brain. We implemented a discrimination task requiring rats to either respond or suppress responding on a lever after the presentation of auditory cues in order to obtain rewards. Single unit activity in the striatal subregions and pre-limbic cortex was recorded using tetrode arrays. Striatal units showed strong onset responses to auditory cues paired with an opportunity to obtain reward. Cue-onset responses in both striatum and cortex were significantly modulated by previous errors suggesting a role of these structures in maintaining appropriate motivation or action selection during ongoing behaviour. Furthermore, failure to respond to the reward-paired tones was associated with higher pre-trial coherence among striatal subregions and between cortex and striatum suggesting a task-negative corticostriatal network whose activity may be suppressed to enable processing of reward-predictive cues. Our findings highlight that coordinated activity in a distributed network including both pre-limbic cortex and multiple striatal regions underlies reward-related decisions.

Cortical Local Field Potential Power Is Associated with Behavioral Detection of Near-threshold Stimuli in the Rat Whisker System: Dissociation between Orbitofrontal and Somatosensory Cortices.

There is growing evidence that ongoing brain oscillations may represent a key regulator of attentional processes and as such may contribute to behavioral performance in psychophysical tasks. OFC appears to be involved in the top-down modulation of sensory processing; however, the specific contribution of ongoing OFC oscillations to perception has not been characterized. Here we used the rat whiskers as a model system to further characterize the relationship between cortical state and tactile detection. Head-fixed rats were trained to report the presence of a vibrotactile stimulus (frequency = 60 Hz, duration = 2 sec, deflection amplitude = 0.01-0.5 mm) applied to a single vibrissa. We calculated power spectra of local field potentials preceding the onset of near-threshold stimuli from microelectrodes chronically implanted in OFC and somatosensory cortex. We found a dissociation between slow oscillation power in the two regions in relation to detection probability: Higher OFC but not somatosensory delta power was associated with increased detection probability. Furthermore, coherence between OFC and barrel cortex was reduced preceding successful detection. Consistent with the role of OFC in attention, our results identify a cortical network whose activity is differentially modulated before successful tactile detection.

Five-Year Sustained Impact of a Thoracic Enhanced Recovery After Surgery Program.

BACKGROUND: Our thoracic enhanced recovery program (ERP) decreased the use of postoperative morphine equivalents and hospital costs 1 year after implementation at our tertiary center. The sustainability and potential increasing benefit of this program were evaluated. METHODS: From 2015 to 2021, we prospectively analyzed the outcomes of patients who underwent elective pleural, pulmonary, or mediastinal operations at our institution. Patients were separated on the basis of the incision (video-assisted thoracoscopic surgery [VATS] or thoracotomy). The ERP protocol was initiated on May 1, 2016, and includes preoperative education, carbohydrate loading, opioid-sparing analgesia, conservative fluid management, protective ventilation, and early ambulation. Outcomes of patients before (2015, pre-VATS and pre-thoracotomy) and after (May 1, 2016, to December 31, 2021, ERP-VATS and ERP-thoracotomy) ERP implementation were compared. RESULTS: The cohort included 1079 patients (pre-ERP era, n = 224 [21%]; ERP era, n = 855 [79%]). There was a median reduction of 1.5 hospital days per patient for ERP-thoracotomy and 1 hospital day per patient for ERP-VATS. Median postoperative morphine equivalents decreased in both groups (125 vs 45 mg, in ERP-thoracotomy; 84 vs 23 mg, ERP-VATS; P < .001), as did total admission cost ($32,118 vs $23,775, ERP-thoracotomy; $17,367 vs $11,560, ERP-VATS; P < .001). Median total fluid balance during the hospital stay decreased significantly. Rates of postoperative atrial fibrillation and urinary retention decreased across both subgroups. CONCLUSIONS: ERP for thoracic surgery is sustainable and has been demonstrated to improve patient outcomes, to decrease opioid use, and to lower hospital costs. Therefore, it has the potential to become the standard of care.

Outcomes of Injured Patients Before and After the Institution of a Third-Tier Activation at a Level 1 Trauma Center.

BACKGROUND: We hypothesized that the addition of a third-level trauma activation would improve outcomes by formalizing an evaluation process for patients in need of urgent evaluation who did not meet the criteria for full or partial trauma alert activation. METHODS: Admission records for all trauma patients admitted between 2000 and 2021 were obtained. The gamma alert trauma activation was implemented in 2011. A washout period of 6 months was used to account for adjustment to the new protocol. Propensity score matching was performed based on ISS scores, age, injury mechanism, and best-validated comorbidities to create a balanced patient distribution. Patients with missing data were excluded from this study. The association between era and outcomes was determined using logistic and linear regression analyses. RESULTS: The matched cohort was well balanced (SMD <.1, all balanced covariates) and included 18,572 patients. Patients in the gamma alert era had decreased ED dwell time, hospital length of stay, and intensive care unit (ICU) length of stay. Readmission rates and rates of upgrade to ICU status were reduced in the gamma alert era. This era was also associated with lower rates of renal failure, UTI, and pneumonia. There was no significant difference in mortality following implementation of the gamma alert. DISCUSSION: Implementation of the gamma alert was associated with an improvement in ED dwell times, fewer unplanned admissions to the ICU, decreased readmissions, and a reduction in other in-hospital events. We believe that this reflects improved triage of patients to the ICU and more effective care of trauma patients.

Extracorporeal Life Support Organization Center of Excellence recognition is associated with improved failure to rescue after cardiac arrest.

OBJECTIVE: The influence of Extracorporeal Life Support Organization (ELSO) center of excellence (CoE) recognition on failure to rescue after cardiac surgery is unknown. We hypothesized that ELSO CoE would be associated with improved failure to rescue. METHODS: Patients undergoing a Society of Thoracic Surgeons index operation in a regional collaborative (2011-2021) were included. Patients were stratified by whether or not their operation was performed at an ELSO CoE. Hierarchical logistic regression analyzed the association between ELSO CoE recognition and failure to rescue. RESULTS: A total of 43,641 patients were included across 17 centers. In total, 807 developed cardiac arrest with 444 (55%) experiencing failure to rescue after cardiac arrest. Three centers received ELSO CoE recognition, and accounted for 4238 patients (9.71%). Before adjustment, operative mortality was equivalent between ELSO CoE and non-ELSO CoE centers (2.08% vs 2.36%; P = .25), as was the rate of any complication (34.5% vs 33.8%; P = .35) and cardiac arrest (1.49% vs 1.89%; P = .07). After adjustment, patients undergoing surgery at an ELSO CoE facility were observed to have 44% decreased odds of failure to rescue after cardiac arrest, relative to patients at non-ELSO CoE facility (odds ratio, 0.56; 95% CI, 0.316-0.993; P = .047). CONCLUSIONS: ELSO CoE status is associated with improved failure to rescue following cardiac arrest for patients undergoing cardiac surgery. These findings highlight the important role that comprehensive quality programs serve in improving perioperative outcomes in cardiac surgery.

Transient receptor potential vanilloid 4 channel inhibition attenuates lung ischemia-reperfusion injury in a porcine lung transplant model.

OBJECTIVE: Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel important in many physiological and pathophysiological processes, including pulmonary disease. Using a murine model, we previously demonstrated that TRPV4 mediates lung ischemia-reperfusion injury, the major cause of primary graft dysfunction after transplant. The current study tests the hypothesis that treatment with a TRPV4 inhibitor will attenuate lung ischemia-reperfusion injury in a clinically relevant porcine lung transplant model. METHODS: A porcine left-lung transplant model was used. Animals were randomized to 2 treatment groups (n = 5/group): vehicle or GSK2193874 (selective TRPV4 inhibitor). Donor lungs underwent 30 minutes of warm ischemia and 24 hours of cold preservation before left lung allotransplantation and 4 hours of reperfusion. Vehicle or GSK2193874 (1 mg/kg) was administered to the recipient as a systemic infusion after recipient lung explant. Lung function, injury, and inflammatory biomarkers were compared. RESULTS: After transplant, left lung oxygenation was significantly improved in the TRPV4 inhibitor group after 3 and 4 hours of reperfusion. Lung histology scores and edema were significantly improved, and neutrophil infiltration was significantly reduced in the TRPV4 inhibitor group. TRPV4 inhibitor-treated recipients had significantly reduced expression of interleukin-8, high mobility group box 1, P-selectin, and tight junction proteins (occludin, claudin-5, and zonula occludens-1) in bronchoalveolar lavage fluid as well as reduced angiopoietin-2 in plasma, all indicative of preservation of endothelial barrier function. CONCLUSIONS: Treatment of lung transplant recipients with TRPV4 inhibitor significantly improves lung function and attenuates ischemia-reperfusion injury. Thus, selective TRPV4 inhibition may be a promising therapeutic strategy to prevent primary graft dysfunction after transplant.

Cue competition effects in the planarian.

The learning abilities of planarian worms (Dugesia tigrina) were assessed by using a number of Pavlovian conditioning paradigms. Experiment 1 showed that planaria were susceptible to basic conditioning in that they readily developed a conditioned response to a change in ambient luminance when it was consistently paired with an electric shock over a number of trials. In Experiment 2, the change in luminance was presented in a compound with a vibration stimulus during conditioning. Subsequent tests revealed poor conditioning of the elements compared with control groups in which the animals were conditioned in the presence of the elements alone, an instance of overshadowing. In Experiment 3, pre-training of one of the elements before compound conditioning resulted in blocking of learning about the other element. These results add to other studies that have reported cue competition effects in animal species belonging to different phyla (chordate, mollusk, arthropod), suggesting that learning in these phyla could be ruled by similar principles. The results are discussed adopting an evolutionary-comparative approach.

Attenuation of Stimulated Accumbal Dopamine Release by NMDA Is Mediated through Metabotropic Glutamate Receptors.

Electrically stimulated dopamine release from the nucleus accumbens is attenuated following application of N-methyl-d-aspartate (NMDA), which is likely to be mediated indirectly through intermediary neuronal mechanisms rather than by a direct action on dopamine terminals. On the basis of known modulatory processes in nucleus accumbens, the current experiments sought to test whether the effect of NMDA was mediated through cholinergic, GABA-ergic, or metabotropic glutamatergic intermediate mechanisms. Fast-scan cyclic voltammetry was used to measure electrically stimulated dopamine release in nucleus accumbens of rat brain slices in vitro. Stimulated dopamine release was attenuated by NMDA, confirming previous findings, but this attenuation was unaffected by either cholinergic or GABA-ergic antagonists. However, it was completely abolished by the nonselective group I/II/III metabotropic glutamate receptor antagonist α-methyl-4-carboxyphenylglycine (MCPG) and by the selective group II antagonist LY 341396. Therefore, group II metabotropic glutamate receptors, but not acetylcholine or GABA receptors, mediate the attenuation of stimulated dopamine release caused by NMDA, probably by presynaptic inhibition through receptors located extra-synaptically on dopamine terminals. This provides a plausible mechanism for the documented role of metabotropic glutamate receptor systems in restoring deficits induced by NMDA receptor antagonists, modeling schizophrenia, underlining the potential for drugs affecting these receptors as therapeutic agents in treating schizophrenia.

Implementation of a non-intensive-care unit medical emergency team improves failure to rescue rates in cardiac surgery patients.

OBJECTIVE: Failure to rescue (FTR) is an emerging measure in cardiac surgery, defined as mortality after a postoperative complication. We hypothesized that establishing a medical emergency team (MET) reduced rates of FTR in adults undergoing cardiac surgery. METHODS: All patients (N = 11,218) undergoing a The Society of Thoracic Surgeons index operation at our center (1994-2018) were stratified by pre-MET or MET era based on the 2009 institutional implementation of a MET to respond to clinical decompensation in non-intensive-care patients. Patients missing The Society of Thoracic Surgeons predicted risk of mortality were excluded from all cohorts. Risk adjusted multivariable regression analyzed the association of postoperative complications, operative mortality, and FTR by era. Nearest neighbor propensity score matching utilizing patients' The Society of Thoracic Surgeons predicted risk of mortality was performed to create balanced control and exposure groups for secondary subgroup analysis. RESULTS: In the risk-adjusted multivariable analysis, surgery during the MET era was associated with decreased mortality (odds ratio [OR], 0.51; 95% CI, 0.45-0.77; P < .001), postoperative renal failure (OR, 0.57; 95% CI, 0.46-0.70; P < .001), reoperation (OR, 0.75; 95% CI, 0.59-0.95; P = .017), and deep sternal wound infection (OR, 0.16; 95% CI, 0.04-0.45; P = .002). Surgery performed during the MET era was associated with a decreased rate of FTR in the risk-adjusted analysis (OR, 0.46; 95% CI, 0.34-0.70; P < .001). CONCLUSIONS: The development of an institutional MET program was associated with a decrease in major complications and FTR. These findings support the development of MET programs to improve FTR after cardiac surgery.

Unplanned postoperative catheterization during admission for coronary artery bypass grafting is neither cheap nor benign, but may rescue patients.

OBJECTIVE: Literature describing outcomes of myocardial ischemia after coronary artery bypass grafting is sparse. We hypothesized these patients had more complications and incurred higher costs of care. METHODS: Using adult cardiac surgery data and cardiac catheterization (CathPCI) data from the Virginia Cardiac Services Quality Initiative, we identified patients who underwent unplanned cardiac catheterization after coronary artery bypass grafting from 2018 to 2021. Adult cardiac surgery data were matched to CathPCI data examining earliest in-hospital catheterization. Patients not requiring catheterization served as the control group. RESULTS: We identified 10,597 patients who underwent isolated coronary artery bypass grafting, of whom 41 of 10,597 underwent unplanned cardiac catheterization. A total of 21 of 41 patients (51%) received percutaneous coronary intervention, most commonly for non-ST-elevation myocardial infarction (n = 7, 33%) and ST-elevation myocardial infarction (n = 6, 29%). Postoperative cardiac arrest occurred in 14 patients (40%). In patients who underwent percutaneous coronary intervention, 14 (67%) had a single lesion, 4 (19%) had 2 lesions, and 3 (14%) had 3 lesions. The left anterior descending artery (38%) was the most frequently intervened upon vessel. Patients who underwent catheterization were more likely to require balloon pump support (26% vs 11%), to have prolonged ventilation (57% vs 20%), to have renal failure (17% vs 7.1%), and to undergo reintubation (37% vs 3.8%, all P < .04). There was no statistical difference in operative mortality (4.9% vs 2.3%, P = .2) or failure to rescue (4.9% vs 1.6%, P = .14). Total costs were higher in patients who underwent unplanned catheterization ($81,293 vs $37,011, P < .001). CONCLUSIONS: Unplanned catheterization after coronary artery bypass grafting is infrequent but associated with more complications and a higher cost of care. Therefore, determination of an association with operative mortality in patients with suspected ischemia after coronary artery bypass grafting requires additional study.